Process for the Preparation of Asenapine and Intermediate Products Used in Said Process

ABSTRACT

The invention relates to a novel process for the preparation of asenapine, i.e. trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, as well as to novel intermediate products for use in said process.

This present invention relates to a novel process for the preparation oftrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole,as well as to novel intermediate products for use in said process.

Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole,which is commonly known as asenapine, is a compound havingCNS-depressant activity and having antihistamine and antiserotoninactivities (U.S. Pat. No. 4,145,434 to van den Burg). Thepharmacological profile of asenapine, its kinetics and metabolism, andthe first safety and efficacy studies in human volunteers and inschizophrenic patients have been reviewed (De Boer et al., Drugs of theFuture, 18(12), 1117-1123, 1993). It has been established that themaleate salt of asenapine, known as Org 5222, is a broad-spectrum, highpotency serotonin, noradrenaline and dopamine antagonist.

Asenapine exhibits potential antipsychotic activity and may be useful inthe treatment of depression (see international patent application WO99/32108). A pharmaceutical preparation suitable for sublingual orbuccal administration of asenapine maleate has been described in theinternational patent application WO 95/23600 (Akzo Nobel N.V.).Asenapine maleate is now the subject of clinical studies, making largescale synthesis of the drug substance necessary.

A general methodology for the preparation of asenapine is disclosed inU.S. Pat. No. 4,145,434. Physical-chemical properties of the drugsubstance Org 5222 have been reported (Funke et al.Arzneim.-Forsch/Drug. Res. 40, 536-539, 1990). Additional syntheticmethods for the preparation of Org 5222 and radiolabelled derivativesthereof have also been described (Vader et al., J. Labelled Comp.Radiopharm. 34, 845-869, 1994).

There is a need for synthetic procedures for the preparation ofasenapine which can reliably be carried out on an industrial scale.

The present invention provides a process for the preparation oftrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(Formula I)

characterised in that an E-stilbene derivative of Formula II

is reacted with an azomethine ylide to provide a trans-pyrrolidinederivative of Formula III,

In Formula II and Formula III, R₁ is F, Br or I;

R₂ and R₃ are different and each is selected from H and Cl; andR₄ is H or a hydroxyl protecting group. Subsequent removal of theprotecting group, when present, and treatment under conditions whicheffect an intramolecular ring closure yield the compound of Formula I.

In the definition of Formula II, R₄ can be a hydroxy protecting groupwhich is stable under the reaction conditions leading to thetrans-pyrrolidine derivative of Formula III. Examples of such protectinggroups are the tetrahydropyranyl group, a silyl protecting group or anacyl group. Further examples are known in the art. See, for example,Wuts, P. G. M. and Greene, T. W.: Protective Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999. A preferred protectinggroup is the acyl group, especially the acetyl group.

Throughout this disclosure, compounds represented by structural formulaehaving a pair of bold and hashed wedged bonds, as shown, e.g., in theformula of compounds (I) and (III), refer to the “trans”diastereoisomer. Each of the compounds may exist as a single enantiomerhaving the absolute stereochemical configuration indicated by the wedgedbonds, or having the opposite absolute configuration, or as a mixture ofenantiomers (e.g., racemate) having the relative stereochemicalconfiguration indicated by the wedged bonds.

In a first reaction step of the process of the invention, an E-stilbenederivative of Formula II is reacted in a [3+2] dipolar cycloadditionreaction with an in situ generated azomethine ylide to provide atrans-pyrrolidine derivative of Formula III. It is thought that thereaction proceeds in a concerted manner in which all bonds are createdsimultaneously. Consequently, the stereochemistry is conserved in theproduct. When the reaction is started with an E-stilbene derivative, thetrans pyrrolidine ring is formed exclusively. The stereoselectivity ofthe dipolar addition step in the process of the invention represents alarge advantage with respect to the good overall yield of the process.

The required azomethine ylide, which may be represented by the followingdipolar structure

can be generated, for example, in situ from trimethylamine-N-oxidedihydrate (TMNO.2H₂O) or trimethylamine-N-oxide anhydrate (TMNO) withlithium di-isopropylamide (LDA) or lithium tetramethylpiperidide. Thedipolar addition reaction can be carried out by addition of LDA to amixture of an E-stilbene of Formula II and TMNO in an aprotic solvent,such as tetrahydrofuran. Preferably, LDA is added slowly to control thereaction temperature, preferably below 30° C., and to effect thedissolution of the trimethylamine-N-oxide.

When R₁ is Br or I in Formula II, the dipolar addition using TMNOproduced the pyrrolidine of Formula III in a good yield and purity, andit proved possible to crystallise the resulting pyrrolidine derivativesof Formula III directly from an n-pentane/ethyl acetate mixture or anethanol/water mixture.

In a preferred process, the required azomethine ylide is generated insitu from N-methoxymethyl-N-trimethylsilylmethyl-N-methylamine (Formula3, below) via activation with trifluoroacetic acid or cesium fluoride(Hosomi, A. et al. Chem. Lett. 1117-1120, 1984).

The novel aminomethyl ether (3) can be prepared from the alkylation ofmethylamine by (chloromethyl)trimethylsilane (1) to yield the secondaryamine (2) which can be subsequently treated with formaldehyde inmethanol solution:

The use of reagent (3) offers many advantages. For example, the processof the invention can be carried out with higher throughputs because theaminomethyl ether reagent allows the use of smaller volumes of solvent.Furthermore, the use of reagent (3) provides for a safer method ofsynthesis because the process of generating the azomethine ylide is muchless exothermic as compared to the process using trimethylamine-N-oxide.In addition, reagent (3) does not react to any appreciable extent withthe Z-stilbene derivative so that the synthesis may tolerate more of theZ-isomer.

In a preferred embodiment, the dipolar addition reaction is carried outusing stilbene derivatives of Formula II wherein R₄ represents aprotecting group. The protecting group, such as an acetyl group,deactivates the hydroxy-phenyl group for electrophilic aromaticsubstitution reactions that may compete with the dipolar additionreaction leading to the pyrrolidine of formula II. As a result theoccurrence of side products can be minimised.

In the second step of the process, a trans-pyrrolidine derivative ofFormula IIIA,

is treated under conditions which effect an intramolecular ring closurereaction to producetrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(asenapine, Formula I).

The intramolecular ring closure reaction to form the 7-membered oxepinering of asenapine can be performed with an Ullmann-type reaction, i.e.treatment of a compound of Formula IIIA in a solvent with copper(0)powder, with a copper(I) salt or with a copper (II) salt in the presenceof a base at elevated temperatures (Ma, D., Cai, Q., Organic Letters, 5,3799-3802, 2003; Buck, E., et. al, Organic Letters 4, 1623-1626, 202;Sawyer, J. S., Tetrahedron 5045-5065, 2002). An additive, such asN,N-dimethylglycine, N-methylglycine,2,2,4,4-tetramethyl-3,5-heptanedione (TMHD) or 8-hydroxyquinoline, maybe used to increase the solubility of the copper ions. Suitable basesinclude Cs₂CO₃, K₂CO₃, pyridine, NaOH, KOH or CsF. Useful copper sourcesinclude Cu-powder, CuI, CuBr, CuCl, Cu(CO)₃ (copper(II)carbonate,Cu(OAc)₂ (copper(II)acetate), Cu(OTf)₂(copper(II)trifluoromethanesulfonate), Cu₂O or CuSO₄.

Suitable conditions for complete conversion of a compound of FormulaIIIA to asenapine are the use of CuCl (0.25 eq.), N,N-dimethylglycine(0.25 eq.) and Cs₂CO₃ (1.1 eq.) in refluxing dioxane for about 24 hours.Solvents for use in the Ullman cyclisation reaction on an industrialscale at temperatures between about 80-110° C. are dimethylformamide(DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine,dioxane, toluene, xylene, diethyleneglycoldimethylether (Diglyme),2-methyltetrahydrofuran, and the like.

Preferred reaction conditions for the Ullman cyclisation reaction atindustrial scale are the use of dimethylacetamide or mixtures thereofwith toluene as the solvent system, the use of Cs₂CO₃, NaOH, KOH orK₂CO₃ as the base, and the use of dimethylglycine in combination withcopper(I)chloride as the catalyst.

A particularly useful embodiment of the invention is the process for thepreparation of asenapine of Formula I,

or a salt thereof, in which (E)-2-(2-bromostyryl)-4-chlorophenylacetate,

is reacted in an inert solvent, such as toluene, with the azomethineylide generated in situ fromN-methoxymethyl-N-trimethylsilylmethyl-N-methylamine with the aid oftrifluoroacetic acid to providetrans-N-methyl-4-(2-bromophenyl)-3-(2-acetoxy-5-chlorophenyl)-pyrrolidine,

The pyrrolidine derivative is treated under basic conditions, such asaqueous alkali solution, to remove the acetyl group. Subsequenttreatment of the deprotected pyrrolidine derivative under Ullmannconditions with the aid of a copper(I) salt to effect the intramolecularring closure gives asenapine, which may be optionally converted to apharmaceutically acceptable salt.

Another aspect of the invention provides the novel trans-pyrrolidinederivative of Formula III,

wherein R₁ is F, Br or I; R₂ and R₃ are different and are each selectedfrom H and Cl; and wherein R₄ is H or a hydroxyl protecting group, aspreviously defined, or a salt thereof.

Still another aspect the present invention provides the novelE-stilbene-derivative of Formula II

wherein R₁ is F, Br or I; R₂ and R₃ are different and are each selectedfrom H and Cl; and wherein R₄ is H or a hydroxyl protecting group, aspreviously defined. These stilbene derivatives are useful intermediatesin industrially producing the pharmaceutically active compound ofFormula I, i.e. asenapine.

The E-stilbene derivatives of Formula II can for instance be preparedusing a Wittig reaction in which a triphenylphosphonium halogenide ofFormula IV, below, is reacted with an appropriate salicylic aldehyde ofFormula VI in refluxing solvents such as chloroform, tetrahydrofuran ormixtures thereof with ethanol, in the presence of an equivalent amountof a base, such as diisopropylethylamine, DBU, DABCO, potassiumtert-butoxide or sodium ethoxide, wherein R₁, R₂ and R₃ are each asdefined above for Formula II and III. The Wittig reaction typicallyresults in a mixture of E- and Z-isomers, the best ratio's beingapproximately 70:30. The pure E-isomer (Formula II) may be isolated viachromatography.

The triphenylphosphonium halogenide of Formula IV can be prepared bytreatment of a compound of Formula V, wherein R₁ is F, Br or I, and R₂is H or Cl, and wherein X represents halogen, preferably Cl of Br, withtriphenylphosphine in refluxing toluene solution.

A preferred method of synthesizing E-stilbene derivatives of Formula IIuses a phosphonate ester derivative having Formula VII, below. Thephosphonate ester derivative can be prepared by heating a compound ofFormula V, either neat or using a solvent such as toluene, with anequimolar amount of triethylphosphite (Davidsen, S. K.; Philips, G. W.;Martin, S. F. Organic Syntheses, Coll. Vol. 8, p. 451 (1993); Vol. 65,p. 119).

In a subsequent Wittig-Horner reaction (T. Kawasaki, et al., J. Org.Chem., 66, 1200-1204, 2001; Tet. Lett. 43, 2449, 2001) the phosphonateester of Formula VII is treated in a solvent, such as tetrahydrofuran,with a base, such as potassium tert-butoxide, butyllithium,sodiumhydride or sodiummethoxide, to produce an intermediate stabilizedphosphonate anion which reacts with a salicylaldehyde derivative ofFormula VI to selectively yield an E-stilbene of Formula II.

Suitable salts of asenapine of Formula I and of the trans-pyrrolidinederivatives of Formula III include the salts obtained from thecombination with an organic base, such as trimethylamine, triethylamineand the like. Suitable acid addition salts can be obtained from thetreatment with a mineral acid such as hydrochloric acid, hydrobromicacid, phosphoric acid and sulfuric acid, or with an organic acid suchas, for example, ascorbic acid, citric acid, tartaric acid, lactic acid,maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid,propionic acid, acetic acid and methane sulfonic acid. The preferredacid addition salt of asenapine of Formula I is the maleate salt, i.e.Org 5222.

The invention is illustrated by the following Examples.

EXAMPLES

The following examples are illustrative and non-limiting and representspecific embodiments of the present invention. In each of the examplesbelow, the compound asenapine (Formula I), and its precursor thetrans-pyrrolidine derivative of Formula III, are racemates, and thepairs of bold wedged bonds or bold and hashed wedged bonds used in theirstructural formulae indicate relative stereochemical configuration.

General Methods:

NMR spectra were recorded on a Bruker DPX 400. Chemical shifts arereported in parts per million (ppm). ¹H-NMR chemical shifts arereferenced to TMS as internal standard (abbreviation s singlet; ddoublet; t triplet, dd double doublet, m multiplet). Mass spectra wererecorded on a PE SCIEX API 165. GC chromatograms were obtained using anAgilent HP6890N gas chromatograph outfitted with a Restek RTX-column.HPLC chromatograms were obtained using an Agilent HP1100 liquidchromatograph.

Example 1

A: (2-Bromo-benzyl)-phosphonic acid diethyl ester

2-Bromobenzyl bromide (1048 g, 4.2 mol) was melted in a water bath of60° C. and dissolved in xyleen (734 ml). The solution was heated to 80°C. Next triethyl phosphite (766 ml, 4.46 mol) was added in three equalportions to the reaction mixture in 60 minutes. The mixture was stirredovernight at 110° C. The reaction mixture was co-evaporated twice with400 ml of xylene. The xylene was removed in vacuo at 60° C. The productwas dried in a vacuum oven at 60° C. and was used without furtherpurification.

¹H-NMR: (CDCl₃): 1.33 (6H, t, 2×CH₃); 3.43 (1H, s, CH₂-a); 3.54 (1H, s,CH₂-b); 4.12 (4H, q, 2×CH₂O); 7.17 (1H, m, ArH); 7.34 (1H, m, ArH); 7.55(1H, m, ArH), 7.62 (1H, m, ArH)

³¹P-NMR: (CDCl₃): 23.81

Mass analysis: M+1=307 and 309 (Br-isotopes) found

B: trans-2-bromo-5′-chloro-2′-hydroxystilbene

5-Chlorosalicylaldehyde (188 g, 1.2 mol) was added to a solution of(2-bromo-benzyl)-phosphonic acid diethyl ester (369 g, 1.2 mol) intetrahydrofuran (1500 ml) under nitrogen. A solution of potassiumtert-butoxide (300 g, 2.68 mol) in tetrahydrofuran (3000 ml) was addedwhile keeping the temperature at 33° C. After completion of the reactionwater (1800 ml) was added followed by 4N HCl (450 ml). The organic layerwas washed with sodium carbonate solution (500 ml) and saturated NaClsolution. The organic layer was evaporated under reduced pressure at 50°C. to give trans-2-bromo-5′-chloro-2′-hydroxystilbene (301.9 g, 92%).

¹H-NMR (CDCl₃): 6.70 (1H, d, H-7); 7.12 (1H, d, H-6); 7.15 (1H, t, H-2or H-3); 7.21 (1H, d H-9); 7.35 (1H, t, H-2 or H-3); 7.46 (1H, d, H-8,);7.52 (1H, d, H-5); 7.58 and 7.68 (2×2H, 2×d, H-1 and H-4)

C:trans-N-methyl-2-(2-bromophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine

To a solution of trans-2-bromo-5′-chloro-2′-hydroxystilbene (81 g, 261mmol) in tetrahydrofuran (570 ml) trimethylamine-N-oxide.dihydrate (43.4g, 390 mmol) was added at ambient temperature. Lithium diisopropylamidein heptane/THF (2M, 1070 ml, 2140 mmol) was then added during the courseof 1 hour while maintaining the temperature below 40° C. Aftercompletion of the reaction water (120 ml) was added. Solvent wasevaporated to a small volume after which ethyl acetate (250 ml) wasadded. The pH was adjusted to pH 8 with 18% hydrochloric acid (˜250 ml)and ethyl acetate (250 ml) was added. The organic layer was separatedand the aqueous layer was again extracted with ethyl acetate (2×120 ml).The combined organic layers were washed with water (325 ml) and withbrine, dried (MgSO₄) and then evaporated in vacuo. The resulting oil wascrystallised from ethanol/water (1/1, v/v) to give the title pyrrolidine(62.0 g, 79%). Purity according to HPLC is 99% a/a.

¹H-NMR (MeOD): 2.50 (3H, s, CH₃), 2.52+3.09+3.10+3.45 (4×1H, t, dd, t,t, Ha-5, Hb-5, Ha-6, Hb-6), 3.62+4.14 (2×1H, 2×m, H4+H7), 6.72 (1H, d,H-1), 6.94 (1H, d, H-3), 6.98 (1H, d, H-2), 7.10+7.35 (2×1H, 2×t,H-10+H-9), 7.52+7.58 (2×1H, 2×d, H-8+H-11).

D+E: Asenapine maleate; Org 5222

Process 1:

To a mixture oftrans-N-methyl-2-(2-bromophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine(103 g; 280.8 mmol) and dioxane (520 ml) were added under a nitrogenatmosphere cesium carbonate (109.79 g; 1.2 eq), N,N dimethylglycine (7.2gram; 0.25 eq) and copper iodide (13.36 g; 0.25 eq). The mixture washeated to reflux, stirred for 68 hours at reflux temperature and thenfiltered over dicalite. The dicalite was washed with dioxane (3×50 ml).The dioxane was evaporated, whereupon the residue was dissolved inethanol (1000 ml). Under stirring aqueous hydrobromic acid (48%; 31.5ml) was added to the ethanol solution. The suspension was stirred for 16hours. The crystalline asenapine hydrobromide salt was collected anddried under vacuum. The product was stirred in water (500 ml) whereuponthe pH was adjusted to 8 by the addition of aqueous sodium hydroxide(2N). The water layer was extracted with dichloromethane. The organiclayer was washed with water (200 ml), dried on magnesium sulphate andevaporated. The residue was dissolved in ethanol (50 ml). To thissolution was added a solution of maleic acid (16.6 gram; 142.6 mmol) inethanol (20 ml) and water (6 ml). The mixture was stirred overnight.Ethanol (20 ml) was added to the thick mass and the suspension wasstirred for another hour. The asenapine maleate was collected and driedunder vacuum at 40° C. yielding 44 g (39%). Purity according to HPLC is99.8% a/a.

¹H-NMR (CDCl₃): 2.58 (3H, s, 1-N—CH₃); 3.14 (2H, m, H-3 and H-4); 3.21and 3.62 (m, 2×2H, 2×H-2 and 2×H-5); 6.24 (2H, s, vinylic H′2 of maleicacid), 7.01-7.36 (7H, m, aromatic H′s).

ESI_MSMS: The observed fragments at m/z 44, 166, 194, 201, 215, 220, 229being [C2H6N]+, [C12H6O]+, [C14H10O]+, [C12H6ClO]+, [C13H8ClO]+,[C16H12O]+, [C14H10ClO]

Melting-point: 140° C.

Process 2

Potassium carbonate (6.24 g; 45.0 mmol) and copper-powder (0.96 g; 15.1mmol) were suspended in dimethylacetamide (25 ml). The temperature wasbrought to 140° C. and nitrogen was led through the suspension during 30minutes.trans-N-Methyl-2-(2-bromophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine(15 g; 40.9 mmol) was then added and the reaction mixture was stirredfor 29 hours. The suspension was filtered over dicalite and the solventwas evaporated. The residue was dissolved in toluene (100 ml) and washedtwice with ammonia (50 ml) and with water (50 ml). The toluene layer wasdried on magnesium sulphate and evaporated. The residue was dissolved inethanol (18.2 ml), whereupon a solution of maleic acid (4.83 g; 41.4mmol) in ethanol (5.2 ml) and water (1.82 ml) was added under stirring.After stirring for 16 hours the crystals of asenapine maleate werecollected and dried under vacuum at 40° C. yielding 8.9 g (54%). Purityaccording to HPLC is 99.9% a/a.

¹H-NMR (CDCl₃): 2.58 (3H, s, 1-N—CH₃); 3.14 (2H, m, H-3 and H-4); 3.21and 3.62 (m, 2×2H, 2×H-2 and 2×H-5); 6.24 (2H, s, vinylic H′2 of maleicacid), 7.01-7.36 (7H, m, aromatic H′s).

ESI_MSMS: The observed fragments at m/z 44, 166, 194, 201, 215, 220, 229being [C2H6N]+, [C12H6O]+, [C14H10O]+, [C12H6ClO]+, [C13H8ClO]+,[C16H12O]+, [C14H10ClO].

Melting-point: 140° C.

Process 3

To a solution oftrans-N-Methyl-2-(2-bromophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine(10 g; 27.3 mmol) in methanol (100 ml) was added KOH (1.68 g, 29.9mmol). The obtained clear solution was stirred at 40° C. for 15 minutes.The solvent was evaporated, toluene (73 ml) and DMA (18 ml) was added,followed by CuCl (1.00 g, 10 mmol), dimethylglycine (2.20 g, 21.3 mmol)and potassium carbonate (3.77 g, 27.3 mmol). After refluxing for 4hours, the solvent was removed in vacuo. The reaction mixture wasdissolved in toluene (55 ml) and extracted with 5% ammonia solution(3×55 ml). The toluene layer was dried on magnesium sulphate andevaporated. The residue was dissolved in 2-propanol (10 ml), whereupon asolution of maleic acid (3.48 g; 30.0 mmol) in 2-propanol (68 ml) andwater (1.82 ml) was added under stirring. After stirring for 16 hoursthe crystals of asenapine maleate were collected and dried under vacuumat 40° C. yielding 6.0 grams (55%). Purity according to HPLC is 99% a/a.

¹H-NMR (CDCl₃): 2.58 (3H, s, 1-N—CH₃); 3.14 (2H, m, H-3 and H-4); 3.21and 3.62 (m, 2×2H, 2×H-2 and 2×H-5); 6.24 (2H, s, vinylic H′2 of maleicacid), 7.01-7.36 (7H, m, aromatic H′s).

ESI_MSMS: The observed fragments at m/z 44, 166, 194, 201, 215, 220, 229being [C2H6N]+, [C12H6O]+, [C14H10O]+, [C12H6ClO]+, [C13H8ClO]+,[C16H12O]+, [C14H10ClO].

Melting-point: 140° C.

Example 2

A: (2-Iodo-benzyl)-phosphonic acid diethyl ester

Triethyl phosphite (ca 66.6 ml; 94% pure; ca. 396.8 mmol) and2-iodobenzyl chloride 1 (100 g, 400 mmol; melted prior to use) weremixed with xylene (65 ml) in a 250 ml roundbottomed flask. The clearsolution was heated to reflux while stirring for 24 hours. The reactionwas followed by GC and ¹H-NMR (CDCl₃). The disappearing proton resonanceof 2H, s, CH₂I at 4.73 ppm and the new 2H, d, CH₂PO(OEt)₂ at 3.47 ppmwere indicative for the progress of the reaction.

¹H-NMR (CDCl₃): 1.33 (6H, t, 2×CH₃); 3.47 (2H, d, CH₂PO(OEt)₂); 4.12 (q,4H, 2×CH₂O); 6.99 (1H, m, ArH); 7.35 (1H, m, ArH); 7.54 (1H, m, ArH),7.89 (1H, m, ArH).

Mass analysis: M+1=355 (Cl-isotopes found), M−1=355 (Cl-isotopes found),

B: trans-2-Iodo-5′-chloro-2′-hydroxystilbene

The resulting solution of crude (2-iodo-benzyl)-phosphonic acid diethylester was cooled to room temperature and then added to a solution of5-chlorosalicylaldehyde (62.14 g, 396.8 mmol; 1.0 eq.) in THF (1000 ml).The solution was cooled with an ice bath to ca. 0° C. KOtBu (97.2 g, 868mmol, 2.19 eq.) was added in portions over 5 minutes and an orange,almost clear solution was obtained. Additional THF (100 ml) was added.After stirring for an additional 10 minutes the ice bath was removed andreaction mixture was stirred while warming to room temperature. After 1hour water (250 ml) was added and a clear orange solution was obtained.Ethyl acetate (400 ml) was added followed by saturated aqueous NaCl (100ml). The organic phase was separated and concentrated under vacuum togive 155 g (>100%) oil. Then, 2N HCl (aq.; 250 ml) was added followed byethyl acetate (250 ml). The organic phase was separated, dried withNa₂SO₄, and evaporated under vacuum to give 127 g solid. This solid wasthen stirred in n-pentane (500 ml) for 15 minutes at room temperature.The beige solid was filtered over a glass filter, washed with n-pentane(50 ml) and dried under vacuum at the rotary evaporator. The yield ofthe title stilbene was 111 grams (79%). The product was used withoutfurther purification.

Mass analysis: M+1=356 (Cl-isomer found).

¹H-NMR (CDCl₃): 6.8.1 (1H, d, H-7); 7.05 (1H, d, H-6); 7.18 (1H, t, H-2or H-3); 7.22 (1H, d H-9); 7.34 (1H, t, H-2 or H-3); 7.42 (1H, d, H-8,);7.60 (1H, d, H-5); 7.52 and 7.98 (2×2H, 2×d, H-1 and H-4)

C:trans-N-methyl-2-(2-iodophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine

A mixture of trans-2-iodo-5′-chloro-2′-hydroxystilbene (56.1 grams,157.6 mmol) and trimethylamine N-oxide dihydrate (52.55 g, 472.8 mmol)was dissolved in THF (570 ml) at room temperature while stirring. Notall of the trimethylamine N-oxide dihydrate dissolved. The mixture wascooled with an ice bath to 0° C. Then, a cooled LDA solution of ca. 4°C. (577.5 ml, 1.8 M in heptane/THF/ethylbenzene; 1.04 moles) was addeddrop wise with a dropping funnel over 25 minutes. The internaltemperature rose to ca. 20-26° C. After the addition was complete thetemperature of the resulting orange/yellow solution dropped to ca. 8° C.within 10 minutes. A sample was taken, quenched with some water andanalyzed by LC to show >90% cycloadduct The ice-bath was removed and thereaction mixture was stirred for an additional 4 hours while warming toroom temperature. Water (140 ml) was added and the mixture was stirredovernight at room temperature. Then 2 N HCl (200 ml) was added followedby ethyl acetate (500 ml). The organic layer was separated. The aqueouslayer, which was still slightly basic (pH indicator paper), was againextracted with ethyl acetate (100 ml). The combined organic extractswere dried with Na₂SO₄. Evaporation under vacuum gave an oil. Diethylether (100 ml) was added to give a solution. Upon addition of n-pentane(300 ml) to this ether solution while stirring gave a yellowprecipitate. Filtration over a glass filter and washing with n-pentane(2×25 ml) gave after drying under vacuum the pure cycloadduct (46.5 g,112.6 mmol; LC>95% pure) as a yellow solid in 72% yield. M.p.: 123.1° C.(onset), 126.9° C. (peak). The filtrates were combined and evaporatedunder vacuum to give 23 grams oil, which contained a lot of productaccording to NMR analysis. Purification by chromatography on silica gel,eluting with ethyl acetate gave a second crop (17 g; 41.1 mmol; 26%).The overall yield was ca. 98%.

Mass analysis: M+1=414 (Cl-isomer found), M−1=412 (Cl-isomer found),

¹H-NMR (CDCl₃): 2.60 (3H, s, CH₃), 2.30+2.96+3.77+3.42 (4×1H, t, dd, t,t, Ha-5, Hb-5, Ha-6, Hb-6), 3.22 (2H, m, H4+H7), 6.82 (1H, d, H-1), 6.92(1H, d, H-3), 7.02 (1H, d, H-2), 7.32+7.15 (2×1H, 2×t, H-10+H-9),7.51+7.85 (2×1H, 2×d, H-8+H-11).

D: Asenapine

Process 1

A mixturetrans-N-methyl-2-(2-iodophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine(46.5 g 112.6 mmol) and cesium carbonate (100 grams, 306.9 mmol) inN,N-dimethylacetamide (DMA, 350 ml) was heated to 140° C. (internaltemperature) while stirring. After 2 hours no Asenapine was observed byNMR analysis of a small sample; only starting material was present.Then, again cesium carbonate (98 g) was added (in total 607.7 mmolCs₂CO₃; used) and the mixture was heated overnight (16 hours). Accordingto NMR analysis a mixture of starting material and Asenapine wasobtained. The product was subjected to purification by chromatography.¹H-NMR (CDCl₃) was in full agreement.

Process 2

A mixture oftrans-N-methyl-2-(2-bromophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine(27 g, 65.4 mmol), cesium carbonate (42.7 g, 131 mmol,) CuI (4.98 g,26.2 mmol) and TMHD (2.39 g, 13.1 mmol, 20 mol %) in NMP (250 ml) washeated to 160° C. (internal temperature). After 1 hour the reaction wascomplete. After 4 hours the mixture was then concentrated under vacuumwith a Kugelrohr apparatus to remove most of the NMP. ¹H-NMR (CDCl₃) wasin full agreement.

Example 3

A+B: trans-2-Acetoxy-2′-bromo-5′-chlorostilbene

2-Bromo-5-chloro-benzylbromide (462 g, 1625 mmol) was heated in triethylphosphite (297 g, 1769 mmol) for 2 hours at 115° C. The mixture wascooled down. To salicylaldehyde (216 g, 1769 mmol) in tetrahydrofuran(4610 ml) at −10° C. was added portionwise KOtBu (495 g, 4411 mmol). Themixture mentioned above was added at −10° C. The reaction mixture wasstirred for 2 hours and then acetic anhydride (461 g, 4516 mmol) wasadded. After 15 minutes of stirring hydrogen chloride (2900 ml 1N, 2900mmol) was added. The layers were separated and the organic layer waswashed with brine (2 L). The organic layer was concentrated undervacuum. The product was crystallized from ethanol (4250 ml) at 20° C. to−10° C. The product was isolated by filtration and dried under vacuumfor 24 hours. Yield 514.8 g (90%) of the title stilbene. Purityaccording to HPLC is >99.5% a/a.

¹H-NMR (CDCl₃): 2.39 (3H, s, CH₃), 7.03 (1H, d, J=16 Hz, olefin H), 7.10(2H, m, H3+H4), 7.30+7.35 (2×1H, t, t, H2+H3), 7.39 (1H, d, J=16 Hz,olefin H), 7.49+7.56+7.68 (3×1H, d, d, d, H4′+H3′+H6′)

Melting Point: 134-135° C.:

Mass: M+1=351 and 353 (Br-isotopes) found.

C:trans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorophenyl)-pyrrolidine

trans-2-Acetoxy-2′-bromo-5′-chlorostilbene (1189 g, 3381 mmol) wasdissolved in toluene (5350 ml) and trifluoroacetic acid (10.42 ml, 165mmol) at 33° C. N-methoxymethyl-N-trimethylsilyl-N-methylamine (670 g,4153 mmol) was added in the course of 1 hour. The organic layer wasconcentrated under vacuum to an oil. This oil was dissolved in methanol(4160 ml) at 30° C. Potassium hydroxide (209 g, 3725 mmol) in water (900ml) was added. After 30 minutes, the pH was adjusted to 8-9 with 3N HCl(approx. 200 ml). The mixture was stirred for 30 minutes and filtered.The product was dried for 24 h under vacuum, yielding the titlepyrrolidine in 1188 grams (96%). Purity according to HPLC is >99.0% a/a.

¹H-NMR: (CDCl₃) 2.25 (1H, t, H1a), 2.53 (3H, s, CH₃),2.86+3.25+3.31+3.67+4.05 (5×1H, t, d, m, t, m, H1b+H4a+H3+H4b+H2),6.62+6.82+6.92+7.08+7.12+7.35+7.42 (7×1H, t, d, d, t, t, d, d, aromaticprotons).

Melting Point: 167° C.

Mass: M+1 366 and 368 (Br-isomers) found.

D+E: Asenapine maleate Process 1

In a 250 mL round-bottomed flask wastrans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorophenyl)-pyrrolidine(10.0 g, 27.3 mmol), cesium carbonate (11.0 g, 33.8 mmol),copper(I)chloride (1.0 grams, 10.10 mmol) and N,N-dimethylglycine (2.2g, 21.33 mmol) in N,N-dimethylacetamide (22 ml) to give a brownsuspension. The slurry was degassed with nitrogen and heated to 50° C.Toluene (88 ml) was added and the slurry was heated to 111° C. for 12-14hours. When the reaction was complete (monitored by HPLC), the mixturecooled to 20° C. 90 ml of 3N ammonia was added and the mixture wasstirred for 15 minutes. The aqueous layer was discarded. The organiclayers were washed with 2×60 ml of 3N ammonia. The toluene layer wasstirred for 30 minutes with ECOSORB GL-793 polymeric carbon (1.0 grams)and then filtered. The toluene was removed by vacuum distillation.2-Propanol (10.0 ml) was added and vacuum distilled to remove thesolvent and to leave asenapine as a yellowish oil. Maleic acid (3.5 g,30.2 mmol) was dissolved in 2-propanol (55 ml) at 45-50° C. Thissolution was added to the yellow oil at 45-50° C. The solution wascooled to 10° C. over 3 hours and held at 10° C. for 2 hours. The solidswere filtered and washed with 40 ml cold (0-5° C.) 2-propanol. Thesolids were dried at 40° C. to afford a white solid. Weight: 8.8 gramsThe asenapine maleate was recrystallized by dissolving the crude productin acetone (51.5 ml) at 55-60° C. and then slowly adding n-heptane (17.5ml). Seed crystals were added and the mixture was stirred for an hour.Further n-heptane (43 ml) was added in the course of 1 hour while thetemperature was maintained at 55-60° C. The mixture was stirred for anhour at this temperature and then cooled to 10° C. over 6 hours. Afterstirring for at least one hour at 10° C., the product was isolated byfiltration and washed with of a 1:1 mixture of acetone and n-heptane (9ml) which had been cooled to 5-15° C. The material was then dried in avacuum oven at 60° C. Yield 8.8 g (88%) of asenapine maleate(orthorhombic crystal form). Purity according to HPLC 99.0%

¹H-NMR: (CDCl₃) 3.07 (3h, s, CH₃), 3.94 (6H, br s, pyrrolidine protons),6.27 (2H, s, maleate protons), 7.00-7.26 (7H, m, aromatic protons).

Melting-point: 140-141° C.

Process 2

To a 250 mL flask,trans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorophenyl)-pyrrolidine(5 g, 13.6 mmol), powdered Cs₂CO₃ (0.8 g, 2.5 mmol), powdered potassiumcarbonate (5.4 g, 29 mmol), CuCl (0.5 g, 5 mmol), N,N-dimethylglycine(1.1 g, 10.6 mmol) and N,N-dimethylacetamide (11 mL) were charged. Theslurry is degassed with nitrogen and heated to 50° C. To the reactionmixture degassed toluene (44 mL) and water (1.5 mL) were added and thenthe resulting slurry was heated to 110-112° C. for 5-10 hours. Thereaction is cooled to room temperature and 3 N aqueous ammonia (45 mL)was added and was stirred for 15 minutes. Separate the layer and washthe organic layer with 3 N aqueous ammonia (2×30 mL). The toluene isremoved under vacuum to produce an oil. The salt is made in 2-propanolas described above.

Process 3

To a 500 mL flask were chargedtrans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorophenyl)-pyrrolidine(10 g, 27.2 mmol), CuCl (1.0 g, 10.2 mmol), potassium carbonate (7.52 g,54.4 mmol), N,N-dimethylglycine (2.2 g, 21.3 mmol) and 22 mLN,N-dimethylacetamide (22 ml). The slurry was degassed with nitrogen for20 minutes and heated to 50° C. Degassed toluene (90 mL) was addedfollowed by 2-methyltetrahydrofuran (10 mL). The mixture was heated to110-115° C. for 4-5 hours with vigorous agitation. The reaction mixturewas cooled to 20° C. Ammonium hydroxide (3N, 90 mL) was added. Themixture was filtered through celite. Methyl THF (20 mL) was added to thefiltrate. The organic layer was washed two additional times withammonium hydroxide (3N, 60 mL). Toluene was removed by vacuumdistillation at 70-80° C. to give an oil. The salt is made in 2-propanolas described above.

Process 4

To a 500 mL flask were charged oftrans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorophenyl)-pyrrolidine(10 g, 27.3 mmol), CuCl (1.0 g, 10.1 mmol), potassium carbonate (7.52 g,54.4 mmol), N,N-dimethylglycine (2.2 g, 21.3 mmol) and dimethylformamide(50 mL). The mixture was heated to 110-115° C. for 3-4 hours. Thereaction was monitored by HPLC until the starting material was less than2%. The reaction mixture was cooled to 20° C. Toluene (50 mL) was addedfollowed by aqueous 3N NH₄OH (90 mL) and stirred for 20 minutes. Thelayers were separated. The aqueous layer was washed with toluene (3×50mL). The combined organic layers were washed with 3N NH₄OH (3×60 mL).Toluene was removed by vacuum distillation at 70-80° C. to give an oil.The salt is made in 2-propanol as described above.

Example 4

A: Methyl-trimethylsilanylmethyl-amine

A pressure flask (500 ml) was charged with chloromethyltrimethylsilane(100 ml, 716 mmol) and 40% aqueous methylamine (373 ml, 4.29 mol). Thereaction was heated to 85° C. for 6 hours, the reaction generates lessthan 690 mbar. The reaction was cooled to 20° C. and the layers wereseparated. The aqueous layer was cooled to 5° C. and solidpotassiumhydroxyde (34 g, 0.607 mol) was added. The aqueous layer waswashed with 1:1 pentane:t-butyl methyl ether (200 ml). The combinedorganics were concentrated in vacuo to about half volume. The productwas distilled at 95-100° C.; yielding 38 grams (50%) ofmethyl-trimethylsilanylmethyl-amine (the product contains 10% mol/molMTBE).

¹H-NMR: (CDCl₃) 0.00 (9H, s, Si(Me₃)), 0.61 (1H, s, NH), 1.99 (2H, s,CH₂), 2.42 (3H, 2, NMe).

Mass: M+1 118 found.

B: N-methoxymethyl-N-trimethylsilyl-N-methylamine

To a cooled solution (0° C.) of formaldehyde (37% in water, 8.5 grams)was added slowly a solution of methyl-trimethylsilanylmethyl-amine (205g, 175 mmol) the temperature of the reaction mixture was below 5° C.Methanol (14 ml) was added, followed by potassium carbonate (12 g).After stirring for one hour the layers were separated. To the organiclayer potassium carbonate (2 grams) was added and the organics werestirred for two hours. The potassium carbonate was removed by filtrationand the product was distilled at 45° C. and 20 mbar.

¹H-NMR: (CDCl₃) 0.00 (9H, s, SiMe₃), 2.00 (2H, s, CH₂Si), 2.30 (3H, s,MeN), 3.25 (3H, s, OMe), 3.88 (2H, s, CH₂O).

Mass: M+1 162 found.

Example 5

A+B: trans-2-bromo-2′-acetoxy-5′-chlorostilbene

2-Bromobenzyl bromide (25 g, 0.100 mol) and toluene (25 ml) were heatedto 100° C. Next triethyl phosphite (19.3 ml, 0.108 mol) was added over30 minutes, while the temperature was kept below 116° C. The mixture wasstirred for 2 hours at 115° C., while the toluene was distilled. Themixture was cooled to room temperature and diluted with THF (37.5 ml).KOtBu (30.5 grams, 0.250 mol) was dissolved in THF (176 ml) and cooledto −10° C. The (2-bromo-benzyl)-phosphonic acid diethyl ester-solutionwas added at 5° C. Next chlorosalicylaldehyde (17.2 g, 0.110 mol) in THF(62 ml) was added at 5° C. The mixture was stirred for one hour at −5°C. to 0° C. When the reaction was complete acetic anhydride (28.3 ml,0.301 mol) was added and the temperature was allowed to rise to 20° C.The reaction was complete in one hour and the mixture was cooled to 5°C. Next 250 ml 1N HCl is added rapidly. The organic layer is washed with200 ml saturated NaCl solution. The organic layer is evaporated underreduced pressure at 50° C., yielding the title stilbene in 25.8 grams,(73%).

¹H-NMR (CDCl₃): 2.38 (3H, s, H-11); 6.87 (1H, d, H-9), 7.19+7.34 (2×1H,2×t, H-2+H-3), 7.26 (1H, d, H-6), 7.46 (1H, d, H-8), 7.60 (2H, dd,H-1+H-4), 7.68 (1H, d, H-5).

C:trans-N-methyl-2-(2-bromophenyl)-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine

trans-2-Bromo-2′-acetoxy-5′-chlorostilbene (26 g, 73 mmol) was slurriedin toluene (91 ml) at 33° C. Trifluoroacetic acid (200 microliters) wasadded. The N-methoxymethyl-N-trimethylsilyl-N-methylamine (14.5 g; 89.7mmol) was added to the reaction mixture over 90 minutes. After addition,the reaction was washed with water (25 ml). The toluene was removed byvacuum distillation. Ethanol (30 ml) was added and removed under reducedpressure. The oil was dissolved in methanol (90 ml). Potassium hydroxide(5 grams in 25 ml water)) was added. The product began to precipitateimmediately. After 30 minutes, the pH was adjusted to 8-9 with 3N HCl (8ml). Added water (10 ml) and cooled to less than 10° C. Filtered andwashed with 1:1 methanol:water. Dried in vacuum to 26.0 grams (96%yield). Purity according to HPLC is 98% a/a.

¹H-NMR (MeOD): 2.50 (3H, s, CH₃), 2.52+3.09+3.10+3.45 (4×1H, t, dd, t,t, Ha-5, Hb-5, Ha-6, Hb-6), 3.62+4.14 (2×1H, 2×m, H4+H7), 6.72 (1H, d,H-1), 6.94 (1H, d, H-3), 6.98 (1H, d, H-2), 7.10+7.35 (2×1H, 2×t,H-10+H-9), 7.52+7.58 (2×1H, 2×d, H-8+H-11).

D+E: Asenapine

See examples 1 or 3 step D+E

Example 6

A: 5-chloro-2-fluoro-benzylbromide

5-Chloro-2-fluoro-toluene (100 g, 692 mmol) was dissolved inethylacetate (300 ml) at 20° C. To this solution N-bromosuccinimide(147.7 g, 830 mmol) and dibenzoyl peroxide (2 g, 8.25 mmol) was added.The mixture was stirred at 80° C. for 3 hours. Heptane (300 ml) wasadded and the solution was cool to 0° C. whereupon succinimideprecipitates. After filtration and washing with heptane, the residue waswashed with water (1500 ml). The filtrate was concentrated in vacuo todryness, yielding 162 grams of crude 5-chloro-2-fluoro-benzylbromide.Purification of the crude product (141 grams) was done by vacuumdistillation at 99° C. and 33 mbar, this 5-chloro-2-fluoro-benzylbromide(99 grams, 75%). Purity according to GC is 87.1% a/a.

¹H-NMR (CDCl₃): 4.44 (2H, d, CH₂), 7.01 (1H, t, H3), 7.26 (1H, m, H4),7.38 (1H, m, H6)

B: (5-chloro-2-fluoro-benzyl)-phosphonic acid diethyl ester

5-Chloro-2-fluoro-benzylbromide (630 g, purity according to GC 72% a/a,2.42 mol) was heated at 100° C. and triethylphosphite (403 g, 2.42 mol)was added slowly in 1 h 45. The mixture was stirred for 2 hours at 100°C., and slowly THF (350 ml) was added and distilled off, until noethylbromide was detected by NMR. To isolate the crude(5-chloro-2-fluoro-benzyl)-phosphonic acid diethyl ester the reactionmixture was cooled to room temperature, yielding 681 grams (100%).

C: trans-5-chloro-2-fluoro-2′-hydroxystilbene

To a solution of potassium tert-butoxide (1088 g, 9.69 mol) intetrahydrofuran (7 l) was added in 17 minutes at 0° C. crude(5-chloro-2-fluoro-benzyl)-phosphonic acid diethyl ester (680 g, 2.42mmol) in tetrahydrofuran (3 l). To this reaction mixture a solution ofsalicylaldehyde (325 g, 2.66 mol) in tetrahydrofuran (3 l) was addedover 1 hour. After stirring for 3 hours at 0° C. the reaction wascomplete. HCl (2M, 3 l) was added at 0° C. to obtain a acidic solution(pH=4.5). At 20° C. the organic phase was isolated, dried over magnesiumsulphate, filtered and concentrated under reduced pressure.Coevaporation with heptane (2×700 ml) provides crudetrans-5-chloro-2-fluoro-2′-hydroxystilbene, which is purified by addingMTBE (6.5 L) and NaOH (238 g) in 7.5 L. After stirring for 3.5 hours theorganic layer was washed with HCl (1M, 5 L) followed by saturated NaClsolution (4 L). Concentration under reduce pressure affordstrans-5-chloro-2-fluoro-2′-hydroxystilbene (460 grams, 69%). Purityaccording to GC is 84% a/a.

¹H-NMR (CDCl₃): 6.79 (1H, dd, H1), 6.95 (1H, m, H3), 6.99 (1H, dd, H7),7.15 (1H, m, H6), 7.17 (1H, m, H2), 7.21 (1H, d, H8), 7.44 (1H, d, H9),7.54 (1H, dd, H4), 7.61 (1H, dd, H5)

Mass analysis: [M+C₃H₅]⁺=289 and 291 [M+C₂H₅]⁺=277 and 279, [M+H]⁺=249and 251, (Cl-isotopes found), and [MH-HCl]⁺=213.

D: trans-N-methyl-2-(2-phenol)-3-(2-fluoro-5-chlorophenyl)-pyrrolidine

Process 1 using trimethylamine-N-oxide.dihydrate

To a solution of trans-5-chloro-2-fluoro-2′-hydroxystilbene (451 grams,1.81 mol) in tetrahydrofuran (2.5 L) trimethylamine-N-oxide.dihydrate(272.9 g, 2.45 mol) was added at 5° C. Lithium diisopropylamide incyclohexane (2M, 3.6 l, 3.62 mol) was then added during the course of 1hour while maintaining the temperature at 5° C. After completion of thereaction saturated NH₄Cl (1.8 l) was added at −10° C. in 30 min. Theorganic solvent was evaporated and the obtained mixture, with a pH of 10was extracted with ethyl acetate (2 l). Concentration under reducedpressure provides crudetrans-N-methyl-2-(2-phenol)-3-(2-fluoro-5-chlorophenyl)-pyrrolidine,which was dissolved in ethanol/water (855 mL, 3/7 v/v) at 80° C., slowlycooling was applied until 0° C. to recrystallizetrans-N-methyl-2-(2-phenol)-3-(2-fluoro-5-chlorophenyl)-pyrrolidine. Thecrystals were isolated, and after drying under reduced pressure to gavethe title pyrrolidine (207 grams, 40%). Purity according to GC 98.2%a/a.

¹H-NMR (CDCl₃): 2.44 (1H, m, H5), 2.54 (1H, s, CH₃), 2.90 (1H, t, H6),3.19 (1H, d, H6), 3.33 (1H, m, H7), 3.56 (1H, m, H5), 3.61 (1H, m, H4),6.65 (1H, m, H10), 6.79 (1H, dd, H11), 6.90 (1H, dd, H8), 6.98 (1H, m,H1), 7.12 (1H, m, H9), 7.17 (1H, dd, H3), 7.18 (1H, m, H2)

Process 2 using trimethylamine-N-oxide anhydrate

Trimethylamine-N-oxide anhydrate was prepared in-situ fromtrimethylamine-N-oxide dihydrate by coevaporation of water with toluene.To a solution of trans-5-chloro-2-fluoro-2′-hydroxystilbene (80 g, 320mmol) in tetrahydrofuran (440 ml) trimethyl-amine-N-oxide anhydrate (48g, 640 mmol) was added at 5° C. Lithium diisopropylamide in cyclohexane(1.5 M, 853 ml, 1.28 mol) was then added during the course of 5 h 30hour while maintaining the temperature at 5° C. After completion of thereaction saturated NH₄Cl (320 ml) was added at −10° C. in 30 min. Theorganic solvent was evaporated and the obtained mixture, with a pH of 10was extracted with ethyl acetate (355 ml). Concentration under reducedpressure provides crudetrans-N-methyl-2-(2-phenol)-3-(2-fluoro-5-chlorophenyl)-pyrrolidine,which was dissolved in ethanol/water (855 mL, 3/7 v/v) at 80° C., slowlycooling was applied until 0° C. to recrystallizetrans-N-methyl-2-(2-phenol)-3-(2-fluoro-5-chlorophenyl)-pyrrolidine. Thecrystals were isolated, and after drying under reduced pressure to gavethe title pyrrolidine (90.2 g, 92%). Purity according to GC 93.5% a/a.

¹H-NMR (CDCl₃): 2.44 (1H, m, H5), 2.53 (1H, s, CH3), 2.90 (1H, t, H6),3.19 (1H, d, H6), 3.34 (1H, m, H7), 3.56 (1H, m, H5), 3.61 (1H, m, H4),6.64 (1H, m, H10), 6.79 (1H, dd, H11), 6.90 (1H, dd, H8), 6.98 (1H, m,H1), 7.12 (1H, m, H9), 7.17 (1H, dd, H3), 7.18 (1H, m, H2)

Mass analysis: [M+C₃H₅]⁺=346 and 348, [M+C₂H₅]⁺=334 and 336, [M+H]⁺=306and 308 (Cl-isotopes found),

E and F Asenapine maleate

A mixture oftrans-N-methyl-2-(2-phenol)-3-(2-fluoro-5-chlorophenyl)-pyrrolidine (205g; 0.67 mol) and potassium hydroxide (44 g; 0.78 mol) inN-methylpyrrolidone (2 l) was heated at 150° C. under nitrogen for 6hours. After completion of the reaction the mixture was cooled 20° C.Water was added (7.2 l) to and extracted with ethyl acetate (2×3 l). Theorganic layers were washed with water and saturated NaCl, concentratedunder reduce pressure to afford crude asenapine in 187 grams yield.Purification was done by crystallisation as the HBr-salt: crudeasenapine was dissolved in acetone (930 ml). Slowly 47% HBr in water (77ml) was added. The suspension was heated to 36° C. to obtain a clearsolution and after cooling, filtering and drying under vacuum at 50° C.asenapine bromide salt was isolated in 143 grams yield (58%). Purityaccording to GC is 94.8%. To obtain Org 5222, the bromide salt (134grams, 0.36 mol) was neutralized with 28% aqueous solution of ammonia inwater (700 ml). The free base was extracted with ethylacetate (2×500 ml)and the organic layer was washed with saturated NaCl. And concentratedunder reduced pressure to yield 104 grams of asenapine, as the freebase. The free base was dissolved in ethanol (208 ml) and heated to 60°C. Maleic acid (46.5 grams 0.40 mol) was added and the mixture wasstirred for 2 h at −15° C. whereupon the maleate precipitates. Thecrystals were collected by filtration, washed with ethanol (208 ml) anddiisopropylether (208 ml). To obtain the desired polymorph the isolatedcrystals were dissolved in ethanol (180 ml) and water (20 ml) at 55° C.The temperature was reduced to 20° C. and the desired polymorph wasprecipitated slowly over 48 h. The crystals were filtered, wash withethanol (100 ml) and dry under reduced pressure at 40° C. Yield 92 grams(36%). Purity according to HPLC 99.8% a/a.

¹H-NMR (MeOD): 3.14 (3H, s, CH₃), 3.79+4.08 (2×2H, 2×m, H2+H5), 3.93(2H, m, H4+H7), 6.24 (2H, s, vinylic H′s of maleic acid), 7.35-7.13 (7H,m, aromatic H′s)

1. The trans-pyrrolidine derivative of Formula IIIA,

or a salt thereof, wherein R₁ is F, Br or I; and R₂ and R₃ are differentand are each selected from H and Cl.
 2. The trans-pyrrolidine derivativeof claim 1, which istrans-N-methyl-2-bromophenyl-3-(2-hydroxy-5-chlorophenyl)-pyrrolidine.3. The E-stilbene-derivative of Formula II,

wherein R₁ is F, Br or I; R₂ and R₃ are different and are each selectedfrom H and Cl; and R₄ is H or a hydroxyl protecting group.
 4. Thecompound N-methoxymethyl-N-trimethylsilylmethyl-N-methylamine.